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Review
.2016 Nov 23:50:329-346.
doi: 10.1146/annurev-genet-120215-034943.

Proteopathic Strains and the Heterogeneity of Neurodegenerative Diseases

Affiliations
Review

Proteopathic Strains and the Heterogeneity of Neurodegenerative Diseases

Lary C Walker. Annu Rev Genet..

Abstract

Most age-related neurodegenerative diseases are associated with the misfolding and aberrant accumulation of specific proteins in the nervous system. The proteins self-assemble and spread by a prion-like process of corruptive molecular templating, whereby abnormally folded proteins induce the misfolding and aggregation of like proteins into characteristic lesions. Despite the apparent simplicity of this process at the molecular level, diseases such as Alzheimer's, Parkinson's, Creutzfeldt-Jakob, and others display remarkable phenotypic heterogeneity, both clinically and pathologically. Evidence is growing that this variability is mediated, at least in part, by the acquisition of diverse molecular architectures by the misfolded proteins, variants referred to as proteopathic strains. The structural and functional diversity of the assemblies is influenced by genetic, epigenetic, and local contextual factors. Insights into proteopathic strains gleaned from the classical prion diseases can be profitably incorporated into research on other neurodegenerative diseases. Their potentially wide-ranging influence on disease phenotype also suggests that proteopathic strains should be considered in the design and interpretation of diagnostic and therapeutic approaches to these disorders.

Keywords: Alzheimer's disease; Aβ; Parkinson's disease; amyloid; prion; synuclein; tau.

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Figures

Figure 1.
Figure 1.
Abnormal protein deposits detected immunohistochemically in three human neurodegenerative diseases.a: Extracellular Aβ (senile) plaques (brown) and intracellular neurofibrillary tangles (purple) in Alzheimer’s disease.b: Intracellular Lewy bodies (arrows) in Lewy body dementia.c: Ectopic (cytoplasmic) mass of TDP-43 (arrowhead) in amyotrophic lateral sclerosis. Nissl counterstain (blue) inb; Bars = 50μm ina andb, 20μm inc.
Figure 2.
Figure 2.
Amyloid.a: Light micrograph of an amyloid plaque in the brain of an Alzheimer patient showing characteristic orange-green birefringence under illumination using crossed polarizing filters (Congo red stain, Nissl counterstain (blue); Bar = 50μm).b: Electron micrograph of massed amyloid fibrils in a plaque from an Alzheimer patient. The average width of amyloid fibrils in vivo is 7–13 nm (17). Bar = 200 nm.
Figure 3.
Figure 3.
The pathology of Creutzfeldt-Jakob disease. Common features of CJD are spongiform degeneration (seen as holes ina; hematoxylin and eosin stain) and the variable accumulation of prion protein (b; PrP immunostain, brown, Nissl counterstain, blue). Both types of lesion vary in type and extent among patients, and amyloidper se is rare in most cases of human prion disease. Bar = 50μm for both panels.
Figure 4.
Figure 4.
Schematic diagram of proteopathic strain formation. Pathogenic proteins are most likely to misfold from an unfolded or partially folded state. The path to a given strain is influenced by such factors as sequence differences, truncation of the protein, post-translational modifications, and the milieu in which the seeds form and propagate. As the molecules acquire excess β-sheet, they bind to one another and multimerize into small oligomers, protofibrils, and/or amyloid fibrils. In addition to their influence on disease presentation, different molecular strains are sometimes reflected in the presence, distribution, and/or morphology of resultant lesions in the brain.
Figure 5.
Figure 5.
Aβ deposits in AD are heterogeneous. A dense-core (amyloid) plaque is marked by an arrow, a cluster of diffuse Aβ deposits by an arrowhead, and a blood vessel with mural and perivascular Aβ by an asterisk. Immunostain for Aβ (brown); Nissl counterstain (blue). Bar = 100μm.
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